Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro

[Image: see text] Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor active against blood stage Pf3D7 parasites. To establish structure–activity relationships for PfPK6 and PfGSK3, 52 analogues were synthesized and assessed for the inhibition of PfGSK3 and PfPK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual PfGSK3/PfPK6 inhibitors 23d (PfGSK3/PfPK6 IC(50) = 172/11 nM) and 23e (PfGSK3/PfPK6 IC(50) = 97/8 nM) with antiplasmodial activity (23dPf3D7 EC(50) = 552 ± 37 nM and 23ePf3D7 EC(50) = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual PfPK6/PfGSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.